Adapting proteostasis for disease intervention     

Balch WE  Morimoto RI  Dillin A  Kelly JW 《Science (New York, N.Y.)》2008,319(5865):916-919

The protein components of eukaryotic cells face acute and chronic challenges to their integrity. Eukaryotic protein homeostasis, or proteostasis, enables healthy cell and organismal development and aging and protects against disease. Here, we describe the proteostasis network, a set of interacting activities that maintain the health of proteome and the organism. Deficiencies in proteostasis lead to many metabolic, oncological, neurodegenerative, and cardiovascular disorders. Small-molecule or biological proteostasis regulators that manipulate the concentration, conformation, quaternary structure, and/or the location of protein(s) have the potential to ameliorate some of the most challenging diseases of our era.  相似文献   

Hereditary early-onset Parkinson's disease caused by mutations in PINK1     

Valente EM  Abou-Sleiman PM  Caputo V  Muqit MM  Harvey K  Gispert S  Ali Z  Del Turco D  Bentivoglio AR  Healy DG  Albanese A  Nussbaum R  González-Maldonado R  Deller T  Salvi S  Cortelli P  Gilks WP  Latchman DS  Harvey RJ  Dallapiccola B  Auburger G  Wood NW 《Science (New York, N.Y.)》2004,304(5674):1158-1160

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.  相似文献   

Antioxidants in photosynthesis and human nutrition   总被引：3，自引：0，他引：3  

Demmig-Adams B  Adams WW 《Science (New York, N.Y.)》2002,298(5601):2149-2153

The harnessing of solar energy by photosynthesis depends on a safety valve that effectively eliminates hazardous excess energy and prevents oxidative damage to the plant cells. Many of the compounds that protect plant cells also protect human cells. Improving plant resistance to stress may thus have the beneficial side effect of also improving the nutritional quality of plants in the human diet. The pathways that synthesize these compounds are becoming amenable to genetic manipulation, which may yield benefits as widespread as improved plant stress tolerance and improved human physical and mental health.  相似文献   

The structural basis of ribozyme-catalyzed RNA assembly     

Robertson MP  Scott WG 《Science (New York, N.Y.)》2007,315(5818):1549-1553

Life originated, according to the RNA World hypothesis, from self-replicating ribozymes that catalyzed ligation of RNA fragments. We have solved the 2.6 angstrom crystal structure of a ligase ribozyme that catalyzes regiospecific formation of a 5' to 3' phosphodiester bond between the 5'-triphosphate and the 3'-hydroxyl termini of two RNA fragments. Invariant residues form tertiary contacts that stabilize a flexible stem of the ribozyme at the ligation site, where an essential magnesium ion coordinates three phosphates. The structure of the active site permits us to suggest how transition-state stabilization and a general base may catalyze the ligation reaction required for prebiotic RNA assembly.  相似文献   

Genome-wide insertional mutagenesis of Arabidopsis thaliana   总被引：2，自引：0，他引：2  

Alonso JM  Stepanova AN  Leisse TJ  Kim CJ  Chen H  Shinn P  Stevenson DK  Zimmerman J  Barajas P  Cheuk R  Gadrinab C  Heller C  Jeske A  Koesema E  Meyers CC  Parker H  Prednis L  Ansari Y  Choy N  Deen H  Geralt M  Hazari N  Hom E  Karnes M  Mulholland C  Ndubaku R  Schmidt I  Guzman P  Aguilar-Henonin L  Schmid M  Weigel D  Carter DE  Marchand T  Risseeuw E  Brogden D  Zeko A  Crosby WL  Berry CC  Ecker JR 《Science (New York, N.Y.)》2003,301(5633):653-657

Over 225,000 independent Agrobacterium transferred DNA (T-DNA) insertion events in the genome of the reference plant Arabidopsis thaliana have been created that represent near saturation of the gene space. The precise locations were determined for more than 88,000 T-DNA insertions, which resulted in the identification of mutations in more than 21,700 of the approximately 29,454 predicted Arabidopsis genes. Genome-wide analysis of the distribution of integration events revealed the existence of a large integration site bias at both the chromosome and gene levels. Insertion mutations were identified in genes that are regulated in response to the plant hormone ethylene.  相似文献   

Molecular confinement accelerates deformation of entangled polymers during squeeze flow     

Rowland HD  King WP  Pethica JB  Cross GL 《Science (New York, N.Y.)》2008,322(5902):720-724

The squeezing of polymers in narrow gaps is important for the dynamics of nanostructure fabrication by nanoimprint embossing and the operation of polymer boundary lubricants. We measured stress versus strain behavior while squeezing entangled polystyrene films to large strains. In confined conditions where films were prepared to a thickness less than the size of the bulk macromolecule, resistance to deformation was markedly reduced for both solid-glass forging and liquid-melt molding. For melt flow, we further observed a complete inversion of conventional polymer viscosity scaling with molecular weight. Our results show that squeeze flow is accelerated at small scales by an unexpected influence of film thickness in polymer materials.  相似文献   

South Carolina's challenge to civil rights: The case of South Carolina State College, 1945–1954     

William C. Hine 《Agriculture and Human Values》1992,9(1):38-50

South Carolina State College was founded in 1896. As one of the Black institutions taking advantage of the Second Morrill Act of 1890, a large portion of the college's limited financial resources, its energies, and its programs were devoted to training students in agriculture, home economics, vocational trades, and in the education of teachers. These curriculums were considered appropriate for young Black men and women in the late nineteenth and early twentieth centuries.When the civil rights movement began to challenge segregation in education in South Carolina in the late 1940s and early 1950s, the state's white leaders responded quickly and effectively by creating graduate and law programs at State College. To preserve the racial status quo and segregation in education, Governor James F. Byrnes subsequently raised funds, including one-half million dollars from the Rockefeller sponsored General Education Board, to improve long neglected facilities at State College. A sizable portion of the funds were devoted to the agricultural program.  相似文献   

Potential Cuban agricultural export profile under open trade between the U. S. and Cuba     

Jose Alvarez  William A. Messina Jr. 《Agriculture and Human Values》1993,10(3):61-74

The sweeping changes that have taken place in the Eastern European countries and the former Soviet Union have detrimentally impacted an already weak Cuban economy. The establishment of the Special Period (1990-) embodies increasing austerity, especially in the inputs market. Recent economic liberalization policies in Cuba may lead to a more market-oriented economy, the lifting of the U. S. embargo, and commercial relations between the two countries. There is concern on the potential impact that resumption of trade may have on the U. S. and Florida's agricultural economy. This study implies potential costs for the citrus, sugar, horticultural, and seafood industries in Florida, while potential Florida exports unveil trade opportunities of a large magnitude. Further research is needed to quantify potential benefits and costs. Of special importance is the fate of Cuba's recent program on low-input sustainable agriculture once large amounts of inputs become available.  相似文献   

High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor     

Cherezov V  Rosenbaum DM  Hanson MA  Rasmussen SG  Thian FS  Kobilka TS  Choi HJ  Kuhn P  Weis WI  Kobilka BK  Stevens RC 《Science (New York, N.Y.)》2007,318(5854):1258-1265

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta2-adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.  相似文献   

Spider Mite Detection and Canopy Component Mapping in Cotton Using Hyperspectral Imagery and Spectral Mixture Analysis   总被引：2，自引：1，他引：2  

Fitzgerald  Glenn J.  Maas  Stephan J.  Detar  William R. 《Precision Agriculture》2004,5(3):275-289

Spectral mixture analysis and hyperspectral remote sensing are analytical and hardware tools new to precision agriculture. They can allow detection and identification of various crop stresses and other plant and canopy characteristics through analysis of their spectral signatures. One stressor in cotton, the strawberry spider mite (Tetranychus turkestani U.N.), feeds on plants causing leaf puckering and reddish discoloration in early stages of infestation and leaf drop later. To determine the feasibility of detecting the damage caused by this pest at the field level, AVIRIS imagery was collected from USDA-ARS cotton research fields at Shafter, CA on 4 dates in 1999. Additionally, cotton plants and soil were imaged in situ in 10 nm increments from 450 to 1050 nm with a liquid-crystal tunable-filter camera system. Mite-damaged areas on leaves, healthy leaves, tilled shaded soil, and tilled sunlit soil were chosen as reference endmembers and used in a constrained linear spectral mixture analysis to unmix the AVIRIS data producing fractional abundance maps. The procedure successfully distinguished between adjacent mite-free and mite-infested cotton fields although shading due to sun angle differences between dates was a complicating factor. The resulting healthy plant, soil, mite-damaged, and shade fraction maps showed the distribution and relative abundance of these endmembers in the fields. These hardware and software technologies can identify the location, spatial extent, and severity of crop stresses for use in precision agriculture.  相似文献